Mar 14, 2013 ... Clinical radiobiology and Tolerance doses for large dose. Hypofractionated
radiation therapy. Prof. Jolyon Hendry. Clinical Radiobiologist ...
Clinical radiobiology and Tolerance doses for large dose International Atomic Energy Agency Hypofractionated radiation therapy
Prof. Jolyon Hendry Clinical Radiobiologist, Christie Hospital Medical Physics and International Atomic Energy Agency Engineering, Manchester UK.
Chapter 5: “In hindsight” “Perthes (1904) in Germany recommended treatment in one session or at most a few fractions. This method, called the expedited (~4 fractions) or massive–dose (single) treatment, led to toxic reactions of unexpected severity. There followed a growing awareness of the time factor – the influence of the time during which a dose was delivered on its biological effect. The first clinical demonstration of the diminished effect of a fractionated dose was published by Krönig & Friedrich (1918). Subsequently, a battle raged for twenty-odd years between the partisans of fractionated doses and those of full (single)-dose treatments.” Summarised in Thames HD: Acta Oncol. 1988;27(2):89-103 3/14/2013
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h Howard T
ames
“The introduc.on of LQ into clinical prac.ce in the 1980s revolu.onised thinking and diversity in radiotherapy”
HYPER
HYPO 3/14/2013
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1987
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Non-standard fractionation… Hypofractionation: Dose per fraction > 2 Gy Fewer fractions
Especially good for tumours with α/β less than for Late reactions
Hyperfractionation: Dose/fraction < 1.8-2 Gy More fractions Longer treatment time Accelerated:
More fractions/week Reduced treatment time
Good for most tumours Good for fastergrowing tumours
All schemes are aimed at improving Therapeutic Index in specific cases 3/14/2013
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Altered dose frac.ona.on schedules
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Bernier and Bentzen 2003
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The “Rs” of Radiotherapy 1. Repair 2. Redistribution 3. Repopulation 4. Reoxygenation
Rodney Withers 1974
5. Radiosensitivity
Gordon Steel 2002
6. Radiated Volume
Wolfgang Dörr & Bert Van der Kogel 2009
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Fractionated doses
Hall & Giaccia 2006: Radiobiology for the Radiologist. 3/14/2013
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Early reactions (and tumours) High α/β
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Late reactions
Low α/β
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Iso-Effectiveness (LQ model) E = n1 (αd1 + βd12) = n2(αd2 + βd22) D1 α + d1 β
= D2 α + d2 β
E=effect n=number of fractions D=dose per fraction α/β=fractionation sensitivity
BED = D 1 + d = D x R.E. (Relative Effectiveness) α /β e.g. EQD210 3/14/2013
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Alpha/Beta Ratios for Early and Late Endpoints in Different Tissues
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Fowler 2005
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α/β ratios for Human Tumors
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DOSE-FRACTIONATION SENSITIVITY OF PROSTATE CANCER DEDUCED FROM RADIOTHERAPY OUTCOME OF 5969 PATIENTS IN SEVEN INTERNATIONAL INSTITUTIONAL DATASETS: α/β = 1.4 (0.9-2.2) Gy R Miralbell, SA Roberts, E Zubizarreta, JH Hendry (Int. J. Rad. Onc. Biol. Phys. 82, e17-‐24, 2012)
60
70
80
EQD2 (2Gy Fx)
90
1 .8
Androgen depriva.on
0
.2
.4
.6
.8 0
.2
.4
.6
.8 .6 .4 .2 0
5 Year bRFS
High risk
1
Intermediate risk
1
Low risk
60
70
80
EQD2 (2Gy Fx)
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90
60
70
80
EQD2 (2Gy Fx)
90
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Prostate External beam + HDR Brachy (3,252 patients)
• Black line, visual regression trend • Points at far right are for HDR BT only! – 9 x 6 Gy
50
60
• Low risk, green; Inter, purple; High, red • Circles, ASTRO; squares, Phoenix • α/β = 1.42 Gy from EBRT analysis
5 year bNED 70 80
• EBRT + HDR BT, filled points + 95%CI
90
100
• EBRT, open points, dashed lines
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80
100
120 140 EQD2
160
180
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Tolerance doses (~1% incidence) – “large” fields Site Digestive system:
Organ/tissue
Latency
EQD2 (Gy)
1 week
1 year
55-60
Salivary glands Esophagus Stomach Small intestine
Liver Skin:
Skin burns (large areas)
Urinary tract:
Nervous system:
Brain necrosis
QUANTEC report, IJROBP 76, Supplement, 2010; ICRP report 118, 2012 3/14/2013
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28 overexposed patients in Panama
Early rectal reactions
75
90
110
125
150
EQD2 Gy
Borras et al. Int. J. Rad. Oncol. Biol. Phys. 59, 539 (2004) 3/14/2013
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Radiosurgery • Small volumes allow high doses to be tolerated; and delivered in a few high-dose fractions • LQ model underestimates normal tissue tolerance at high dose per fraction? • Hypoxia in tumours causes resistance to shortcourse few fractions?
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Tolerance doses
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Gay et al 2009 Rad Onc 91, 369
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Human fractionation parameters – Cyberknife sites Tumor Site
Normal tissue OAR
α/β ratio (Gy)
T1/2 (2) hours
Head & neck
10
4
5
Prostate
1.5
4R
-
Brain
?
?
>4
Lung
?
3
?
Spinal cord
?
2
>5
Pancreas, Liver, Kidney
?
?
?
In: Basic Clinical Radiobiology. Eds: Joiner & van der Kogel, 2009 3/14/2013
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Sci. Transl. Med. 2010
All data fitted
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≤3.25 Gy data fitted
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Mouse lung pneumonitis: fractions every 3 hours Thames 1984: assumed T1/2=1.5 hours, LQ + incomplete repair
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Wang 2010: took T1/2=0.4 hours, gLQ model
Thames re-analysis in 1993 gave T1/2 (1) = 0.40 h (0.28, 0.53) and T1/2 (2) = 4.01 h (1.55, 6.57 CI). 80% of repair is fast. J Hendry Hypo SRS
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Conclusion If you want to project to high fractional doses: options: • Use an “incomplete repair” version (Thames) • Use a higher α/β value so that curvature is less • Modify the basic LQ model (Wang, Joiner etc) • More complex, use a “biphasic repair” version for every sub-fraction in the schedule (Millar)
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Repair kinetics of DNA strand breaks in CHO cells
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Biphasic repair
Dale & Fowler 2007 3/14/2013
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Biphasic repair: animal systems System
T1/2 (1) hours
T1/2 (2) hours
Author
Pig skin reactions
0.4
1.2
Van den Aardweg
Pig skin reactions
0.2
6.6
Millar et al
Mouse lung
0.4
4.0
Van Rongen
Rat spinal cord
0.7
3.8
Ang et al
Mouse kidney cells
0.2
5.0
Millar et al
Basic Clinical Radiobiology book, 2009 3/14/2013
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Biphasic repair: human systems System
T1/2 (1) hours
T1/2 (2) hours
Author
Skin erythema
0.35
1.2
Turesson & Thames
Skin telangiectasia
0.4
3.5
Turesson & Thames
Skin telangiectasia
-
3.8 (2.5, 4.6)
Bentzen et al
Subcutaneous fibrosis
-
4.4 (3.8, 4.9)
Bentzen et al
Myelopathy
-
>5
Dische & Saunders
Temporal lobe necrosis
-
>4
Lee et al
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Fowler JF. Brit. J. Radiol. 83 554 (2010)
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Loss of BED vs fraction duration – for various fraction sizes (late reactions) Half-time 0.4h+4 h
Half-time 0.2h+4 h
Fowler et al, IJROBP, 59, 242, 2004
Loss of BED vs fraction duration –
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for various fraction sizes (tumours/early)
Fowler et al, IJROBP, 59, 242, 2004
When is a single dose (fraction) not a single dose? – when it is given as multiple variable doses delivered at different dose-rates with multiple variable incomplete repair intervals, as for example by Cyber Knife or Gamma Knife radiosurgery. How do we deal with this from a radiobiological perspective? Modified words of John Hopewell (Oxford) and Bill Millar (Glasgow) 2012
Single dose fraction of 13 Gy
Courtesy J Hopewell & W Millar 2013
Equivalent doses can be calculated using biologically effective dose (BED) equations Thus for true single dose exposure the BED is given by the equation:-
1 ⎡ φ(Ξ,µ1 ) + cφ(Ξ,µ 2 ) ⎤ 2 BED = DT + DT ⎢ ⎥ α/β ⎣ 1+ c ⎦ For a single treatment session with multiple dose fractions involving incomplete repair the BED is given by the equation:-
1 BED = DT + α/β
n φ(Ξ,µ ) + cφ(Ξ,µ ) ⎡ 2 1 2 ⎤ d ∑ i ⎢⎣ ⎥ 1+ c ⎦ i=1
Courtesy J Hopewell & W Millar 2013
Variation in treatment times/protocols for 26 patients with Vestibular Schwannomas using prescription doses of either 10, 12, 13 or 14 Gy Gamma-Knife B-Series (Overall treatment time -mins) 20-30
30-40
40-50
50-60
25.40
-
41.28 40.85
-
60-70
70-80
80-90
> 90
14 Gy 3 iso-centres (2 gaps*) 5 iso-centres (4 gaps) 6 iso-centres (5 gaps) 13 iso-centres (12 gaps)
67.78
129.58
13 Gy 3 iso-centres (2 gaps) 6 iso-centres (5 gaps) 7 iso-centres (6 gaps)
-
54.55 -
61.58
74.91 -
74.89
75.36 92.30 8 iso-centres (7 gaps) 12 Gy 2 iso-centres (1 gap) 4 iso-centres (3 gaps)
-
29.62 -
5 iso-centres (4 gaps) 6 iso-centres (5 gaps) 7 iso-centres (6 gaps) 8 iso-centres (7 gaps) 10 Gy 5 iso-centres (4 gaps) 6 iso-centres (5 gaps) 7 iso-centres (6 gaps) 8 iso-centres (7 gaps)
* Gap standardised to 6 min
32.65 39.97
50.47
38.16
124.25
-
49.79 -
63.07 63.43
73.97 -
80.38
73.93
-
57.21 -
84.61 91.96
Courtesy J Hopewell & W Millar 2013
Three voxels: Same physical prescription dose, different BED values due to protocol variations
Point 3
Point 2
Protocol Coll50% beam dose-rate imator iso-dose time (Gy/min) (mm) (Gy) (min) 1 14
6.45
5.2
2.47
2 4
3.20
2.9
2.22
3 14
6.45
5.2
2.47
Point 1
Courtesy J Hopewell & W Millar 2013
Maximum variation in BED values for individual voxels in a single patient treated with 3 iso-centres, for total isosurface doses, of 14 Gy (prescription dose in 25.4 min) Iso-centre contribution (Gy)
Relative contribution (%)
Dose rate (Gy/min)
BED
Point 1 (max BED)
12.36 (shot 1) 0.17 (shot 2) 1.47 (shot 3)
88.3 1.20 10.5
2.36 0.06 0.28
85.28 (+10.0%)
Point 2 (median BED)
9.55 (shot 1) 4.09 (shot 2) 0.36 (shot 3)
68.2 29.2 2.60
1.82 0.78 0.13
80.83 (+4.2%)
Point 3 (min BED)
6.98 (shot 1) 5.05 (shot 2) 1.97 (shot 3)
49.9 36.0 14.1
1.33 0.96 0.97
77.56 (Reference)
Courtesy J Hopewell & W Millar 2013
Conclusions • There is enough evidence to believe that biphasic repair applies to humans • The shorter T1/2 produces a bigger influence on fraction protraction effects (more sparing) • With few high-dose fractions (SRS), more sparing of normal tissue than tumor if α/βtumor > α/βnormaltissue, and fraction protraction increases that, but the reverse is likely also true in some cases! e.g. prostate versus rectum.
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Carbon ion hypofractionation • Non-small cell lung cancer • 18 fractions/ 6 weeks 9F/ 3 weeks 1F/1d
4F/4 days
• 4F = 4 fields @15 GyE 1 field per day total 60 GyE • 1F = up to 44 GyE >600 patients reported in 2012 Chiba, Japan Okada, J Rad Res 51, 355, 2010; Kamada, Int J Clin Oncol 17, 85, 2012 3/14/2013
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More details Radiobiological principles: their application to γ-knife therapy. Hopewell JW, Millar WT, Lindquist C. Prog Neurol Surg. 2012;25:39-54 On the biologically effective dose (BED) - using convolution for calculating the effects of repair: I. Analytical considerations. Gustafsson J, Nilsson P, Gleisner KS. Phys Med Biol. 2013 Mar 7;58(5):1507 On the biologically effective dose (BED) - using convolution for calculating the effects of repair: II. Numerical considerations. Gustafsson J, Nilsson P, Gleisner KS. Phys Med Biol. 2013 Mar 7;58(5):1529 “Radiobiological Modelling in Radiation Oncology” Editors: Dale RE & Jones B. British Institute of Radiology (2007) “Basic Clinical Radiobiology” Editors: A.J van der Kogel and M.C. Joiner. 4th edition, Hodder Arnold (2009). 3/14/2013
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